Revealing the Immunogenic Risk of Polymers

Li, Bowen; Yuan, Zhefan; Hung, Hsiang-Chien; Ma, Jinrong; Jain, Priyesh; Tsao, Caroline; Xie, Jingyi; Zhang, Peng; Lin, Xiaojie; Wu, Kan; Jiang, Shaoyi

doi:10.1002/anie.201808615

Cited by 99 publications

(91 citation statements)

References 39 publications

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“…The immunogenicity of PEG and the seemingly random induction of APA responses by select PEGylated therapeutics remains poorly understood, and represents an area of active clinical and preclinical research. Current hypotheses point to a number of important factors implicated in the potential APA response including the molecular size of PEG, linker type, number of PEG polymer chains attached, and/or overall immunogenicity of the underlying therapeutic molecule [23][24][25] . Likewise, it remains poorly understood how APA can specifically bind to the highly flexible and hydrophilic PEG polymer, despite the absence of any fixed conformation to which Ab can directly dock to along the PEG polymer backbone.…”

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confidence: 99%

Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

Huckaby

Jacobs

et al. 2020

Commun Chem

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Polyethylene glycol (PEG) is a polymer routinely used to modify biologics and nanoparticles to prolong blood circulation and reduce immunogenicity of the underlying therapeutic. However, several PEGylated therapeutics induce the development of anti-PEG antibodies (APA), leading to reduced efficacy and increased adverse events. Given the highly flexible structure of PEG, how APA specifically bind PEG remains poorly understood. Here, we report a crystal structure illustrating the structural properties and conformation of the APA 6-3 Fab bound to the backbone of PEG. The structure reveals an open ring-like sub-structure in the Fab paratope, whereby PEG backbone is captured and then stabilized via Van der Waals interactions along the interior and exterior of the ring paratope surface. Our finding illustrates a strategy by which antibodies can bind highly flexible repeated structures that lack fixed conformations, such as polymers. This also substantially advances our understanding of the humoral immune response generated against PEG.

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confidence: 99%

Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

Huckaby

Jacobs

et al. 2020

Commun Chem

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“…There are also opportunities for PSBMA–zwitterionic polymers to be an excellent stealth coating for delivering a range of protein therapeutics and without eliciting observable immune response. [ 81,82 ]…”

Section: Discussionmentioning

confidence: 99%

Zwitterionic Polymer Coating Suppresses Microglial Encapsulation to Neural Implants In Vitro and In Vivo

Yang

Eles

et al. 2020

Adv. Biosys.

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For brain computer interfaces (BCI), the immune response to implanted electrodes is a major biological cause of device failure. Bioactive coatings such as neural adhesion molecule L1 have been shown to improve the biocompatibility, but are difficult to handle or produce in batches. Here, a synthetic zwitterionic polymer coating, poly(sulfobetaine methacrylate) (PSBMA) is developed for neural implants with the goal of reducing the inflammatory host response. In tests in vitro, the zwitterionic coating inhibits protein adsorption and the attachment of fibroblasts and microglia, and remains stable for at least 4 weeks. In vivo two‐photon microscopy on CX3CR1‐GFP mice shows that the zwitterionic coating significantly suppresses the microglial encapsulation of neural microelectrodes over a 6 h observation period. Furthermore, the lower microglial encapsulation on zwitterionic polymer‐coated microelectrodes is revealed to originate from a reduction in the size but not the number of microglial end feet. This work provides a facile method for coating neural implants with zwitterionic polymers and illustrates the initial interaction between microglia and coated surface at high temporal and spatial resolution.

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“…Lipid-modified PCBs were synthesized following Scheme 1 based on a previous study. [11] PCBs were obtained by reversible addition-fragmentation chain transfer polymerization. The degree of polymerization was 24 and 22 for PCB1 and PCB3, respectively, equivalent to that of PCB2, which did not induce anti-polymer antibodies when liposome modified.…”

Section: Synthesis Of Lipid-modified Pcbs and Liposome Preparationmentioning

confidence: 99%

“…[10][11] For polymeric compounds with a repeated structure, such as PEG and PCBs, to induce antibody production, B cell receptors (BCRs) on the B cell surface should be crosslinked to induce signaling that activates the B cell [21]. The PEGylated liposome is large enough (approximately 100 nm) to crosslink multiple BCRs.…”

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confidence: 99%

Blood Retention and Antigenicity of Polycarboxybetaine-Modified Liposomes

Ryujin¹,

Shimizu²,

Miyahara³

et al. 2020

Preprint

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<div>Zwitterionic polycarboxybetaines (PCBs) have gained attention as alternative stealth polymers whose</div><div>liposomal formulation and protein conjugates were reported not to elicit anti-polymer antibodies. Here, we</div><div>studied the blood retention and antigenicity of liposomes modified with PCBs focusing on their chemical</div><div>structures and doses. We compared PCBs with either 1 or 3 (PCB1 or PCB3) spacer carbons between the</div><div>carboxylate and ammonium groups. PCB3-modified liposomes had a short blood retention, whereas PCB1-</div><div>modified liposomes demonstrated extended blood retention that was somewhat superior to PEGylated liposome.</div><div>This confirmed the excellent non-fouling nature of PCB1 reported previously. Interestingly, PCB1-liposome as</div><div>well as PCB3-liposome elicited specific IgMs toward each PCB. The dose-dependent production of specific</div><div>IgMs to PCB-liposomes was similar to that of PEGylated liposome, i.e., high doses of PCB-liposomes reduced</div><div>the production of specific IgMs, termed immunological tolerance. These results indicate the importance of</div><div>investigating the effect of dose to clarify the existence of antigenicity of stealth polymers</div>

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Revealing the Immunogenic Risk of Polymers

Cited by 99 publications

References 39 publications

Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

Zwitterionic Polymer Coating Suppresses Microglial Encapsulation to Neural Implants In Vitro and In Vivo

Blood Retention and Antigenicity of Polycarboxybetaine-Modified Liposomes

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